Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 18, Issue 3, Pages 302-U86Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.1986
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Funding
- US National Institute of General Medical Sciences [F32GM087004]
- US National Institutes of Health (NIH) Cellular and Molecular Genetics
- NIH/National Cancer Institute [T32 CA009523]
- UCSD
- NIH [GM071654]
- Keck, Searle, V., Emerald and Peter Gruber Foundations
- California Institute of Regenerative Medicine [RB1-01413]
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The highly conserved let-7 microRNA (miRNA) regulates developmental pathways across animal phyla. Mis-expression of let-7 causes lethality in C. elegans and has been associated with several human diseases. We show that timing of let-7 expression in developing worms is under complex transcriptional and post-transcriptional control. Expression of let-7 primary transcripts oscillates during each larval stage, but precursor and mature let-7 miRNAs do not accumulate until later in development after LIN-28 protein has diminished. We demonstrate that LIN-28 binds endogenous primary let-7 transcripts co-transcriptionally. We further show that LIN-28 binds endogenous primary let-7 transcripts in the nuclear compartment of human ES cells, suggesting that this LIN-28 activity is conserved across species. We conclude that co-transcriptional interaction of LIN-28 with let-7 primary transcripts blocks Drosha processing and, thus, precocious expression of mature let-7 during early development.
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